PROJECT #4. Neuroprotection of Erythropoietin Signaling in TBI Cerebral hypoperfusion plays a role in the injury that develops in contused brain. If the reduction in CBF is severe enough, cerebral ischemic injury develops. If the reduction in CBF is not severe enough to cause oxygen depletion, then the baseline low flow causes the brain tissue to be more vulnerable to secondary ischemic insults. Both circumstances have a well established adverse effect on neurological outcome. In the cortical impact injury model, cerebral hypoperfusion in contused brain is associated with a relative deficiency of nitric oxide (NO) produced by the endothelial isoform of nitric oxide synthase (eNOS). And administration of L-arginine (the substrate for the eNOS) or administration of tetrahydrobiopterin (an essential cofactor of eNOS) results in an increase in the NO concentrations in the brain and restores CBF in the contused brain back to pre-injury values. The improvement in perfusion of the contused brain with Larginine is associated with a reduction in contusion volume. Erythropoietin (Epo) is expressed in the brain after injury, and has several activities that might be neuroprotective. Numerous studies suggest that Epo administration upregulates NOS or increases NO production or dilates vessels in a manner that suggests NO production by endothelium. In physiological circumstances where endogenous Epo production is increased, such as in athletes training at high altitudes, production of NO is also increased. Finally in some pathological conditions, Epo administration has been found to dilate cerebral vessels. In a subarachnoid hemorrhage model, Epo reversed the vasoconstriction that occurred in intracranial vessels. A single dose of Epo has been shown to preserve autoregulation of cerebral blood flow following subarachnoid hemorrhage. The purpose of this study is to investigate these potentially neuroprotective mechanisms of Epo on the vascular dysfunction that occurs after trauma. The specific aims include the following: To study the expression of Epo and Epo receptor (EpoR) by the injured brain. To study the acute effects of augmented Epo signaling on cerebral hemodynamics. To study the chronic effects of augmented Epo signaling on the brain's response to injury. To study the synergistic effects of Epo and EpoR peptide administration on the brain's response to injury.